Joints are one of the common ways bones in the skeleton are connected. The ends of normal articulated bones are covered by articular cartilage tissue, which permits practically frictionless movement of the bones with respect to one another [L. Weiss, ed., Cell and Tissue Biology (Munchen: Urban and Schwarzenburg, 1988) p. 247].
Articular cartilage is characterized by a particular structural organization. It consists of specialized cells (chondrocytes) embedded in an intercellular material (often referred to in the literature as the “cartilage matrix”) that is rich in proteoglycans, collagen fibrils of predominantly type II, other proteins, and water [Buckwalter et al., “Articular Cartilage: Injury and Repair,” in Injury and Repair of the Musculoskeletal Soft Tissues (Park Ridge, Ill.: American Academy of Orthopaedic Surgeons Symposium, 1987) p. 465]. The cartilage matrix is produced and maintained by the chondrocytes embedded within it. Cartilage tissue is neither innervated nor penetrated by the vascular or lymphatic systems. However, in the mature joints of adults, the underlying subchondral bone tissue forms a thin, continuous plate between the bone tissue and the cartilage. This subchondral bone tissue or bone plate is innervated and vascularized. Beneath this bone plate, the bone tissue forms trabeculae, containing the marrow. In immature joints, articular cartilage is underlined by only primary bone trabeculae. A portion of the meniscal tissue in joints also consists of cartilage whose make-up is similar to articular cartilage [Beaupre, A. et al., Clin. Orthop. Rel. Res., pp. 72-76 (1986)].
Two types of defects are recognized in articular surfaces. These are full-thickness defects and superficial defects. Full-thickness defects are those that penetrate into or through the subchondral bone plate; superficial defects are those that do not. These defects differ not only in the extent of physical damage to the cartilage, but also in the nature of the repair response each type of lesion can elicit.
Full-thickness defects of an articular surface include damage to the hyaline cartilage, the calcified cartilage layer and the subchondral bone tissue with its blood vessels and bone marrow. Full-thickness defects can cause severe pain because the bone plate contains sensory nerve endings. Such defects generally arise from severe trauma or during the late stages of degenerative joint disease, such as osteoarthritis. Full-thickness defects may, on occasion, lead to bleeding and the induction of a repair reaction from the subchondral bone [Buckwalter et al., “Articular Cartilage: Composition, Structure, Response to Injury, and Methods of Facilitating Repair,” in Articular Cartilage and Knee Joint Function: Basic Science and Arthroscopy (New York: Raven Press, 1990) pp. 19-56]. The repair tissue formed is a vascularized, fibrous type of cartilage that has poor biomechanical properties, and that does not persist on a long-term basis [Buckwalter et al. (1990), supra].
Superficial defects in articular cartilage tissue are restricted to the cartilage tissue itself. Such defects are notorious because they generally do not heal and show no propensity for repair reactions.
Superficial defects may appear as fissures, divots, or clefts in the surface of the cartilage, or they may have a “crab-meat” appearance in the affected tissue. They contain no bleeding vessels (blood spots) such as are seen in full-thickness defects. Superficial defects may have no known cause, but often they are the result of mechanical derangements that lead to a wearing down of the cartilaginous tissue. Mechanical derangements may be caused by trauma to the joint, e.g., a displacement of torn meniscus tissue into the joint, meniscectomy, a Taxation of the joint by a torn ligament, malalignment of joints, bone fracture or by hereditary diseases. Superficial defects are also characteristic of early stages of degenerative joint diseases, such as osteoarthritis. Because cartilage tissue is not innervated [Ham's Histology (9th ed.) (Philadelphia: J.B. Lippincott Co. 1987), pp. 266-272] or vascularized, superficial defects are typically not painful. However, although painless, superficial defects generally do not heal, and often degenerate into full-thickness defects.
It is generally believed that because articular cartilage lacks a vasculature, damaged cartilage tissue does not receive sufficient or proper stimuli to elicit a repair response [Webber et al., “Intrinsic Repair Capabilities of Rabbit Meniscal Fibrocartilage: A Cell Culture Model”, (30th Ann. Orthop. Res. Soc., Atlanta, February 1984); Webber et al., J. Orthop Res., 3 pp. 36-42 (1985)]. It is theorized that chondrocytes in cartilaginous tissue are normally not exposed to sufficient amounts of repair-stimulating agents such as growth factors and fibrin clots typically present in damaged vascularized tissue.
One approach that has been used to expose damaged cartilage tissue to repair stimuli involves drilling or scraping through the cartilage into the subchondral bone to cause bleeding [Buckwalter et al. (1990), supra]. Unfortunately, the repair response of the tissue to such surgical trauma is usually comparable to that observed to take place naturally in full-thickness defects that cause bleeding, viz., formation of a fibrous type of cartilage that exhibits insufficient biomechanical properties and that does not persist on a long-term basis [Buckwalter et al. (1990), supra].
A variety of growth factors have been isolated and are now available for research and biomedical applications [see e.g., Rizzino, A., Dev. Biol., 130, pp. 411-422 (1988)]. Some of these growth factors, such as transforming growth factor beta (TGF-β), have been reported to promote formation of cartilage-specific molecules, such as type II collagen and cartilage-specific proteoglycans, in embryonic rat mesenchymal cells in vitro [e.g., Seyedin et al., Proc. Natl. Acad. Sci. USA, 82, pp. 2267-71 (1985); Seyedin et al., J. Biol. Chem. 261, pp. 5693-95 (1986); Seyedin et al., J. Biol. Chem., 262, pp. 1946-1949 (1987)].
Millions of patients have been diagnosed as having osteoarthritis, i.e., as having degenerating defects or lesions in their articular cartilage. Nevertheless, despite claims of various methods to elicit a repair response in damaged cartilage, none of these treatments has received substantial application [Buckwalter et al. (1990), supra; Knutson et al., J. Bone and Joint Surg., 68-B, p. 795 (1986); Knutson et al., J. Bone and Joint Surg., 67-B, p. 47 (1985); Knutson et al., Clin. Orthop., 191, p. 202 (1984); Marquet, Clin. Orthop., 146, p. 102 (1980)]. And such treatments have generally provided only temporary relief. Systemic use of “chondroprotective agents” has also been purported to arrest the progression of osteoarthritis and to induce relief of pain [Lohmander, L. S. et al., Ann. Rheum. Dis., 55(7), pp. 424-31 (1996)]. However, such agents have not been shown to promote repair of lesions or defects in cartilage tissue.
One approach that has been considered is illustrated in U.S. Pat. No. 4,846,835. There, chondrocytes are harvested from mature cartilage tissue that has been removed by biopsy, subsequently grown or expanded in number in tissue culture, and then grafted into the defect site in a collagen gel matrix used to fix the chondrocytes in situ. A periosteal sheet is used to secure the transplanted cells (i.e., the graft) in the defect. This approach suffers from the disadvantages of being more invasive than the instant invention, and creating additional cartilage defects by removing mature cartilage. The use of articular chondrocytes to repair defects is also disadvantaged because articular chondrocytes have a more limited potential for proliferation as compared to synovial cells.
Another approach has been to transform bone marrow-derived mesenchymal stem cells to create chondrocytes in vitro for transplantation into a cartilage defect [Caplan and Haynesworth, U.S. Pat. No. 5,811,094]. These cells can only be obtained through a bone-marrow biopsy, which may be associated with long-term local pathology at the donor site of the patient (usually the iliac crest of the pelvis). Biopsied bone marrow cells then must be purified using sophisticated techniques, expanded in vitro and seeded at the site of the defect [See Caplan et al., Clin. Orthop., 342, pp. 254-269(1997)].
A further approach found in the literature is applying an electric potential through the tissue surrounding the defect in order to stimulate the growth of new tissue. [U.S. Pat. No. 4,506,673].
Another approach to repairing such defects is found in U.S. Pat. Nos. 5,270,300, 5,206,023, and 5,368,858, in which the present inventor described inventions wherein repair cells are attracted from the synovial compartment to the defect site, where they are induced to proliferate and to differentiate into chondrocytes that synthesize new cartilage matrix.
It has been reported that one means to retain cells in suspension or a matrix within an articular cartilage defect is to suture an appropriate thin covering membrane on the top of the defect space. The covering membrane material used so far has been periosteum-derived, perichondrium-derived or muscle fascia. These covering membranes or other artificial covering membranes have the significant disadvantage that the covering membrane itself does not transform into cartilage tissue, or does so to only a limited extent. Thus the defect space will never fill completely with repair cartilage. Moreover, the degradation of fibrous types of covering membranes is extremely slow. In addition, these covering membranes do not integrate with the native tissue along the defect lesion borders. Such covering membrane tissue may contain fibroblasts, which will not transform into chondrocytes but instead result in undesirable scar-like tissue. Thus, in certain prior art covering membranes, fibroblasts may migrate out into the repair space, contaminate it and lead to unwanted scar tissue formation.
There is, therefore, a need for a simple, fast, and reliable treatment superficial and full-thickness cartilage defects, e.g., as found in cases of severe mechanical injury and osteoarthritis.